Injectable aqueous ophthalmic composition and method of use therefor

ABSTRACT

The present invention is directed to the provision of an ophthalmic composition suitable for intravitreal injection. The composition includes an amount of complexing agent that reacts with one or more endogenous components (e.g., hyaluronic acid) in the eye to form a mass of enhanced viscosity. This mass can aid in creating a desirable release profile of therapeutic agent.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. application Ser.No. 14/057,125 filed Oct. 18, 2013 (now allowed), which is acontinuation io application of U.S. application Ser. No. 12/886,988filed Sep. 21, 2010 (now abandoned), which claims priority under 35U.S.C. §119 to U.S. Provisional Patent Application Ser. No. 61/244,916,filed Sep. 23, 2009, the entire contents of which are incorporatedherein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention is directed to an injectable aqueous ophthalmiccomposition. More particularly, the present invention is directed to aninjectable aqueous ophthalmic composition that includes a complexingagent (e.g., positively charged polymer or other compound) for enhancingthe drug delivery capabilities of the composition when the compositionis injected in an eye of human or animal.

BACKGROUND OF THE INVENTION

Intravitreal injections are commonly used to deliver therapeutic agentsto the eye, particularly to the vitreous humor of the eye for treatmentof ophthalmic maladies such as age related macular degeneration (AMD),diabetic macular edema (DME), inflammation or the like. Intravitrealinjections are often particularly desirable since they can provideenhanced bioavailability to a target location (e.g., the retina) of theeye relative to other delivery mechanisms such as topical delivery.

While generally providing a desirable form of drug delivery,intravitreal injections also have drawbacks and can present variousdifferent complications. Many therapeutic agents have difficultypenetrating target ocular tissue even after intravitreal injection. Insome instances, the penetration difficulty can be caused by poorsolubility or hydrophilicity of the therapeutic agent. In otherinstances, poor permeability due to size, molecular weight or othercharacteristics of the therapeutic agent can be the cause of poorpenetration.

Intravitreal injections can also suffer from other drawbacks. As one sexample, intravitreal injections having therapeutic agent in the form ofparticles (e.g., suspended submicron particles or nanoparticles) canobstruct vision if the particles disperse in an undesirable manner. Asanother example, it can be difficult to consistently provide therapeuticagent close to a target location with an intravitreal injection sincevarying injection angles and variable eye size can cause io significantvariability in delivery location. As yet another example, intravitrealinjections can result in delivery of undesirably high concentrations oftherapeutic agent to a target location or elsewhere particularly whenthe therapeutic agent is relatively soluble.

In addition to the above, therapeutic agents delivered by intravitrealinjections can lack duration of action since the agents can oftenrapidly disperse within the eye after injection. Such lack of durationis particularly undesirable since it can necessitate greater injectionfrequency.

In view of the above, it would be particularly desirable to provide anintravitreal injection that overcomes one or any combination of theabove discussed drawbacks. As such, the present invention provides anophthalmic composition, a system and a method that allow for a moredesirable intravitreal injection.

SUMMARY OF THE INVENTION

The present invention is directed to an injectable ophthalmiccomposition. The composition typically includes a therapeutic agent, acomplexing agent and water. The complexing agent is typically providedin an amount sufficient to form a mass of enhanced viscosity within avitreous humor of an eye of a human upon injection of the compositioninto the eye. The mass of enhanced viscosity will typically release thetherapeutic agent by virtue of break down of the mass in the vitreoushumor and/or the diffusion of the therapeutic agent out of the mass ofenhanced viscosity. Advantageously, this allows release of thetherapeutic agent over an extended period of time.

The complexing agent is typically positively charged. Preferredcomplexing agents may be selected from poly-amino acids, galactomannanpolymer (e.g., cationic-derivatized galactomannan polymer), a quaternaryammonium compound, a cellulosic polymer or a combination thereof. Suchagent will preferably be capable of complexing with endogenoushyaluronic acid, collagen or both in the vitreous to for the mass ofenhanced viscosity.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated upon the provision of an ophthalmiccomposition that is particularly suitable for delivery as anintravitreal injection. The ophthalmic composition typically includes anophthalmic therapeutic agent, complexing agent and water. Uponinjection, the complexing agent complexes (e.g., ionically interacts)with an endogenous component (e.g., hyaluronic acid) of is the vitreousto form a mass of enhanced viscosity within the vitreous.

Advantageously, the mass can aid in one or more of the following: a)slowing release of the therapeutic agent within the eye; b) inhibitingundesired movement of the therapeutic agent within the eye; c) providinga sustained release vehicle that naturally breaks down in the eye;and/or d) decreasing retinal toxicity of some therapeutic agents bylowering exposure of the retina to high therapeutic concentrations orany combination thereof.

Unless indicated otherwise, all ingredient concentrations are listed as% (w/v).

The therapeutic agent of the ophthalmic composition of the presentinvention will typically exhibit one or more specific characteristicsthat would normally be problematic for delivery of that agent as anintravitreal injection. The therapeutic agent may exhibit a relativelylow degree of solubility due to hydrophobicity or other property of theagent. Alternatively, the therapeutic may exhibit a relatively highdegree of solubility due to hydrophilicity or other property of theagent. Additionally or alternatively, the therapeutic agent may have arelatively high molecular weight, which can affect the ability of theagent to penetrate biological membrane.

The therapeutic agent can be provided in solid, semi-solid or liquidform. It is particularly contemplated that the therapeutic agent may bepresent in solid state as particles (e.g., submicron or nano- particles)and that the complex (e.g., cationic/anionic polymer complex) for withthe complexing agent will entrap the particles and release therapeuticagent by one or more mechanisms, at least some of which are discussedherein. When provided as particles, the average particle size willtypically be at least 1 nanometer and more typically at least about 10nanometers and will typically be less than 10 microns, more typicallyless than 1 micron and even possibly less than about 500 nanometers.

A therapeutic agent having a relatively low degree of solubility for theio present invention means that the therapeutic agent exhibits asolubility in water that is less than 0.01%, more typically less than0.005%. As used herein, solubility in water is to be determined at 25°C. and atmospheric pressure, unless otherwise specifically stated. Theserelatively water insoluble therapeutic agents are typically hydrophobic.As such, these agents will typically have a log D that is greater thanis 0.3, more preferably greater than 0.8, more preferably greater than1.5 and even possibly greater than 2.7 or even greater than 5.0.

As used herein, log D is the ratio of the sum of the concentrations ofall forms of the therapeutic agent (ionized plus un-ionized) in each oftwo phases, an zo octanol phase and a water phase. For measurements ofdistribution coefficient, the pH of the aqueous phase is buffered to 7.4such that the pH is not significantly perturbed by the introduction ofthe compound. The logarithm of the ratio of the sum of concentrations ofthe solute's various forms in one solvent, to the sum of theconcentrations of its forms in the other solvent is called Log D:

log D _(oct/wat)=log([solute]_(octanol)/([solute]_(ionized water)+[Solute]_(neutral water)))

Examples of therapeutic agents having a relatively low degree ofsolubility include, without limitation, the following; steroids (e.g.,corticosteroids) such as dexamethasone, prednisolone (e.g., prednisoloneacetate), fluoro-steroid (e.g., fluorometholone), triamcinoloneacetonide or the like; receptor tyrosine kinase inhibitors (RTKi) withmulti-target binding profiles, such as N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl) urea; and/or prostaglandin Hsynthesis inhibitors (Cox I or Cox II), also referred to ascyclooxygenase type I and type II inhibitors, such as diclofenac,flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indomethacin,naproxen, ibuprofen, bromfenac, ketoprofen, meclofenamate, piroxicam,sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen,ciprofloxacin, benoxaprofen, nabumetome, etodolac, phenylbutazone,aspirin, oxyphenbutazone.

A therapeutic agent having a relatively high degree of solubility forthe present invention means that the therapeutic agent exhibits asolubility in water that is at least 0.3%, more typically at least 1.0%.These relatively water soluble therapeutic agents are typicallyhydrophilic. As such, these agents will typically have a log D that isless than about 0.1, more typically less than about 0.05 and evenpossibly less than about 0.01.

Example of therapeutic agents having a relatively high degree ofsolubility include, without limitation, fluoroquinolones such asmoxifloxacin, vancomycin, gatifloxacin or the like as well as proteinsand/or peptides such as ranizumab bevacizumab or the like as well ascertain anti-viral drugs such as ganciclovir.

A therapeutic agent having a high molecular weight for the presentinvention means that that the average molecular weight of the agent isat least 1000 daltons, more typically at least 10,000 daltons and evenmore typically at least 50,000 daltons. The average molecular weight istypically less than 150,000 daltons and zo possibly less than 80,000daltons. Examples of therapeutic agents having relatively high molecularweights include, without limitation, ranizumab, bevacizumab, pegaptanib(pegaptanib sodium) or the like.

The term complexing agent, as used herein, is a compound that is capableof complexing with one or more endogenous components of the vitreous forforming a mass of enhanced viscosity. The complexing preferably occursthrough ionic interaction (e.g., attraction) between the complexingagent and one or more components of the vitreous although otherinteraction (e.g., chemical reaction) may alternatively or additionallyform the complex. Preferred complexing agent is cationically (i.e.,positively) charged such that it can form an ionic complex withendongenous hyaluronic acid, collagen or both in the vitreous to formthe mass of enhanced viscosity. It is also preferred that the complexingagent be a positively charged polymer. Still further it is preferredthat the complexing agent be biologically compatible. It is alsopreferred that the complexing agent, the complex formed between thecomplexing agent and the endogenous vitreous component (e.g., hyaluronicacid) and the mass of enhanced viscosity formed thereby be bioerodiblewithin the vitreous to aid in the gradual breakdown of the mass and/orcomplex after formation thereof. Formation and breakdown of the massand/or complex are discussed further below.

There are multiple different compounds that may be employed as acomplexing agent. Highly preferred compounds include, withoutlimitation, polyamino acid, galactomannan (e.g., cationic-derivatized),amine compounds, cellulosic compounds (e.g., cationic cellulosiccompounds), quaternary ammonium compounds or any combination thereof. Ofcourse, one complexing agent may be classified in more than one of thesecategories depending upon its chemical io characteristics. Each of thesecomplexing agents can be provided in a polymeric and/or positivelycharged form. The complexing agent will typically be present in thecomposition of the present invention in an amount that is at least 0.01w/v %, more typically at least 0.1 w/v % and even more typically atleast 0.5 w/v %. The concentration of complexing agent will alsotypically be no greater than about 10 is w/v %, more typically nogreater than about 3 w/v % and even possibly no greater than 1.0 w/v %.

Poly-amino acids can include any polymer formed of multiple repeat unitsof amino acid. Examples include, without limitation, polylysine,polyarginine, polyhistidine or the like. When used, polyamino acid istypically present in the composition at a concentration of at least 0.05w/v %, more typically at least 0.2 w/v % and even more typically atleast 0.7 w/v % and a concentration that is typically less than 10.0 w/v%, more typically less than 5.0 w/v % and even more typically less than1.4 w/v %.

Polylysine is a preferred polyamino acid. Polylysine is typically of thefollowing chemical formula II:

(^(I)) (C₆ ¹⁻¹ ₁₂N₂O)_(n) wherein n =2 to 10,000.

Exemplary polylysines include poly-L-lysine, poly-D-lysine, racemicPoly-DL-lysine, derivatives thereof and combinations thereof. It iscontemplated that any of alpha polylysines, epsilon polylysines,poly-L-lysines, poly-D-lysines, any derivatives thereof, anycombinations thereof or the like may be used for the present inventionunless otherwise specifically stated. However, poly-c-L-lysine ispreferred and, as such, the lysine of the composition may be entirely orsubstantially entirely poly-c-L-lysine. The term substantially entirely,as it refers to poly-c-L-lysine means at least 70% by weight and morepreferably at least 90% by weight of the lysine of the composition ispoly-c-L-lysine. Poly-c-L-lysine can be formed in accordance with thefollowing scheme:

Preferably, any polylysine included in the composition will have arelatively high number average molecular weight. The number averagemolecular weight of the polylysine is typically at least 50,000, moretypically at least 150,000 and even possibly at least 300,000.

Another preferred class of complexing agent is positively charged aminecompounds, particularly positively charged amine polymers. Such aminepolymers can be primary, secondary, tertiary amines or a combinationthereof. Such amine compounds or amine polymers can include or bederived from aromatic or zo heterocyclic base groups such as aniline,pyridine or others. Nucleosides and polymers derived therefrom are oneparticularly preferred class of amine compounds suitable as complexingagents for the composition of the present invention. Polysaccharidescontaining amine groups are also preferred for the composition of thepresent invention. Examples of preferred amine containingpolysaccharides include chitosan and water soluble derivatives ofchitosan.

Another preferred class of complexing agent is derivatives of naturalpolymers, which have been modified to be positively charged and/orsoluble in water. Cellulosic polymers are particularly preferred withinthis class. One particularly preferred positively charged cellulosicpolymer is a copolymer of polyethoxylated cellulose and dimethyldiallylammonium chloride and has the Cosmetic, Toiletry and FragranceAssociation (CTFA) designation of Polyquaternium-4. Suitable suchpolymers are sold under the tradename

CELQUAT SC-230M and CELQUAT SC-240C and are commercially available fromAkzo-Nobel. Advantageously, these polymers can be modified to includevarying amounts of nitrogen (i.e., nitrogen substitutions) and, throughthe use of greater or lesser substitutions, the degree of complexing canrespectively be raised or lowered. When included, the positively chargednatural (e.g., cellulosic) polymers are typically present in thecomposition at a concentration that is at least at least 0.01 w/v %,more typically at least 0.05 w/v % and even more typically at least 0.2w/v % and a concentration that is typically less than 4.0 w/v %, moretypically less than 1.0 w/v % and even more typically less than 0.4 w/v%.

Quaternary ammonium compounds may also be used as complexing agents forthe present invention. A variety of quaternary copolymers of varyingquaternization can be synthesized based on homo or copolymers of aminoacrylates with methyl, ethyl or propyl side chains. These monomers couldalso be copolymerized with other nonionic monomers including quaternaryacrylic homopolymers such as homopolymers of 2-methacryloxyethyltrimethylammonium chloride and 2-methacryloxyethyl methyl diethylammonium bromide and copolymers of quaternary acrylate monomers withwater soluble monomers. When included, the quaternary ammonium compoundsare typically present in the composition at a concentration that is atleast at least 0.01 w/v %, more typically at least 0.05 w/v % and evenmore typically at least 0.2 w/v % and a concentration that is typicallyless than 4.0 w/v %, more typically less than 1.0 w/v % and even moretypically less than 0.4 w/v %.

One particularly preferred polymer complexing agent is a polymericquaternary ammonium salt of hydroxyethylcellulose and a trimethylammonium chloride substituted epoxide. This complexing agent is both aquaternary ammonium compound and a cellulosic polymer and has the CTFAdesignation polyquaternium-10. Suitable such polymer is sold under thetradename UCARE JR-30M, which is commercially available from Rhodia orCELQUAT L-200 and H-100, which are commercially available from AkzoNobel. Another suitable quaternary ammonium/cellulosic compound is analkyl modified quaternary ammonium salt of hydroxyethyl cellulose and atrimethyl ammonium chloride substituted epoxide having the CTFAdesignation polyquaternium-24. An example of such polymer is sold underthe tradename QUATRISOFT LM-200 and is commercially available fromAmerchol Corp., Edison, N.J. Other particularly preferred polymercomplexing agents, which are both quaternary ammonium compounds andcellulosic polymers, include various quaternary ammonium salts ofhydroxyethyl cellulose sold under the tradename SOFTCAT and commerciallyavailable from The Dow Chemical Company, Midland, Mich.

Another preferred polymer complexing agent is galactomannan polymer,particularly cationic-derivatized galactomannan polymer, which can alsotypically be considered a cellulosic polymer. Particularly preferred ispositively charged guar. Guar (e.g., guar gum) or other galactomannanpolymer substituted with positively charged chemical moieties areparticularly desirable. Such is galactomannan polymer will typicallyhave a cationic degree of substitution (DS) with a lower limit of 0.01and an upper limit of 3.0%, more preferably a lower limit of 0.1 or 0.3%and an upper limit of 2.5%. The galactomannan, particularly in the caseof guar gum, typically has a number weight average molecular weight (MW)with a lower limit of 50, 000 and an upper limit of about 1,000,000,more preferably a lower limit of 100, 000 or 300,000 and an upper limitof about 700,000. One particularly preferred galactomannan is apositively charged guar gum such as O-[2-hydroxy-3-(trimethylamonium)propyl] chloride guar, which is commercially available under thetradename C261N from Cosmedia. Advantageously, such galactomannanpolymer (e.g., guar gum) compounds will typically exhibit low toxicity.When included, the galactomannan polymer is typically present in thecomposition at a concentration that is at least at least 0.04 w/v %,more typically at least 0.20 w/v % and even more typically at least 0.5w/v % and a concentration that is typically less than 7.0 w/v %, moretypically less than 3.0 w/v % and even more typically less than 1.2 w/v%.

The composition of the present invention may be formulated as asolution, a suspension or otherwise. Typically the composition isaqueous and comprises at least 50% and more typically at least 95%water.

Since the composition of the present invention is typically formulatedto be suitable for intravitreal injection, the composition willtypically be composed of only or substantially only complexing agent,therapeutic agent and water. As used herein, substantially onlycomplexing agent, therapeutic agent and water means that the compositionincludes less than 5.0 w/v %, more typically less than 4.0 w/v % andeven more preferably less than 2.0 w/v % of any ingredients other thatcomplexing agent, therapeutic agent and water.

If other excipients are included, they are typically included in lowconcentrations. Other suitable excipients can include, withoutlimitation, buffers, salts, surface active agents (e.g., surfactants),polymers, tonicity agents, combinations thereof or the like. Forsuspensions, a suspending agent may be employed. Particularly preferredsuspending agents include, without limitation, polymers such aspolysaccharides (e.g., xanthan gum, carboxymethylcellulose, chondroitinsulfate) and carboxyvinyl polymer.

Since the composition of the present invention will typically beadministered as an intravitreal injection, the invention also includes amethod of delivery. In the method, the composition is typically locatedwithin a syringe, the needle of the syringe is then inserted into an eye(e.g., an eye of a human) and the composition is then expelled into theeye. Prior to injection, the composition can be located within thesyringe using the syringe to draw the composition from a unit dosecontainer. Alternatively, a pre-filled syringe can contain thecomposition. An individual (e.g., a doctor) typically inserts the needleinto the eye and then uses a plunger of the syringe to expel thecomposition from inside the syringe into the vitreous (i.e., vitreousfluid) of the eye. Typically the volume of the injection will be atleast 1 μL, more typically at least 10 μL and even possibly at least 100μL and will typically be less than 1000 μL.

Upon delivery, the composition, and particularly the complexing agent,interacts with components of the vitreous to form a mass of enhancedviscosity. As used herein, the term enhanced viscosity suggests aviscosity that is greater than the viscosity of the vitreous fluid atbody temperature (i.e., 37 degrees Celcius). The term also suggests thatthe viscosity of the mass is greater than the viscosity of thecomposition prior to injection. Preferably, the enhanced viscosity is atleast 105%, more typically at least 120% and even more typically atleast 140% the viscosity of the vitreous fluid and/or the composition.The therapeutic agent, upon formation of the mass, is dispersed throughthe mass. For forming the mass of enhanced viscosity, the complexingagent may interact with various components known to be naturally withinthe vitreous, however, it is preferable that the complexing agent atleast interact with endogenous hyaluronic acid, collagen or both withinthe vitreous. In a preferred embodiment, the complexing agent complexeswith the endogenous hyaluronic acid to form a gel (e.g., hydrogel)within the vitreous. For forming this complex, it is highly preferredthat the complexing agent be positively charged.

After formation, the mass of enhanced viscosity breaks down and/or thetherapeutic agent diffuses out of the mass over an extended time periodfor releasing therapeutic agent. For relatively soluble and insolubletherapeutic agents, which may be of various different particles sizes,the extended time period is typically at least two hours, more typicallyat least 8 hours and even possibly at least 24 or 48 hours. The extendedtime period will often be less than 120 or 60 days. Over this timeperiod, the complexing agent and/or the mass of enhanced viscositybreaks down through biodegradation and potentially other mechanisms aswell. Preferably, the lysine, particularly polylysine, breaks down intoits amino acid lysine form such that it can be eliminated from thevitreous through natural pathways.

The mass may be formed in any location within the vitreous. However, formany diseases of the retina, it is desirable that the mass be formedclose to the fovea. As such, it is contemplated that the entire mass beformed within 10 millimeters, more typically within 5 millimeters andeven possibly within 3 millimeters of the fovea.

The present invention can provide a variety of advantages depending uponthe embodiment of the invention. For suspensions, which are typicallyused for the relatively hydrophobic/insoluble therapeutic agents, theenhanced viscosity mass can inhibit the therapeutic agent particles fromsettling to the bottom of the eye. For relatively hydrophilic/solubletherapeutic agents, the enhanced viscosity mass can inhibit dispersionof the therapeutic agent such that larger amounts of therapeutic agentscan be injected at one time without undesirably high amounts of theagent being quickly dispersed within the eye and/or without requiring arelatively high frequency of administration of composition containingtherapeutic agent. It is contemplated that the composition of thepresent invention may be administered less frequently than once every 48hours, more preferably less than once every 5 days, even more preferablyless than once every 10 days, still more preferably less than once every20 days and even possibly less than once every 30 days. The compositionwill typically be administered at least once every 60 days.

Additionally, the complexing agent may have an additional ability toinhibit dispersion of charged therapeutic agents through chargeinteraction.

It has also been found that, depending upon the type of complexing agentin the composition, the amount of complexing agent in the compositioncan be tailored to result in a mass of enhanced viscosity that has adensity substantially similar to the density of the vitreous fluid. Whensuch densities are so matched, the mass of enhanced viscosity willremain substantially stationary relative to the eye for a substantialportion of the extended time period of therapeutic agent release. Insuch an embodiment, the density of the mass upon formation is less than15% and more preferably less than 5% higher or lower than the density ofthe vitreous fluid.

As yet another advantage, the compositions of the present invention canbe more easily injected into the eye relative to other injections. Sincethe mass of enhanced viscosity is formed upon injection rather thatprior to injection, the composition can be more easily injected,particularly through a fine gauge needle, relative to a composition thatis already of enhanced viscosity prior to injection. As still anotheradvantage, the ability of the mass of enhanced viscosity to inhibitrapid dispersion of small particles of therapeutic agent can help thecomposition, zo particularly when formulated as a suspension, avoidobstruction of vision.

The composition, particularly intravitreal injections of thecomposition, can be used to treat a variety of ophthalmic maladies. Itis particularly desirable for treating diseases such as age relatedmacular degeneration (AMD), diabetic macular edema (DME), retinalinfections, viral infections, inflammation, endophthalmitis or the like.

EXAMPLES Example 1

Poly-L-lysine aqueous solution (1%) was injected into a matrix material.The amine groups on the poly-lysine had a pKa value of approximately10.5 and were positively charged and soluble in acidic to neutralsolution with a charge density dependent upon pH. The matrix materialwas formed of vitreous fluid attained from excised pig eyes or rabbiteyes. As such, the matrix material typically included hyaluronic acidand collagen. Upon injection, the poly-L-lysine formed masses ofenhanced viscosity with the hyaluronic acid and/or collagen in the formof gel complexes within the matrix material. Thereafter, each of themasses of enhanced viscosity slowly eroded over various extended timeperiods.

Example 2

Cationic Guar C261N, 1% aqueous solution, was injected into a matrixmaterial. The matrix material was formed of vitreous fluid attained fromexcised pig eyes or rabbit eyes. As such, the matrix material typicallyincluded hyaluronic acid and collagen. Upon injection, the cationic guarformed masses of enhanced viscosity with the hyaluronic acid and/orcollagen in the form of gel complexes within the matrix material.Thereafter, each of the masses of enhanced viscosity slowly eroded overvarious extended time periods.

Example 3

Chitosan and water soluble derivatives of chitosan such as lactatechitosan and carboxy methyl chitosan were injected into a matrixmaterial. The amine groups on the chitosan had a pKa value ofapproximately 6.5 and were positively charged and soluble in acidic toneutral solution with a charge density dependent upon pH and % degree ofacetylation-value. The matrix material was formed of vitreous fluidattained from excised pig eyes. As such, the matrix material typicallyincluded hyaluronic acid and collagen. Upon injection, the chitosan andits derivatives each formed masses of enhanced viscosity with thehyaluronic acid and/or collagen in the form of gel complexes within thematrix material. Thereafter, each of the masses of enhanced viscosityslowly eroded over various extended time periods.

Example 4

Various grades of quaternary ammonium salts of hydroxyethylcellulose(SOFTCAT polymers) were injected into the matrix material described inexample 1. The polymers each formed masses of enhanced viscosity withthe hyaluronic acid and or collagen in the form of gel complexes withinthe matrix material. Thereafter, each of the masses of enhancedviscosity slowly eroded over various extended time periods.

Example 5

Various grades of CELQUAT polymers were injected into the matrixmaterial described in example 1. The polymers each formed masses ofenhanced viscosity with the hyaluronic acid and/or collagen in the formof gel complexes within the matrix material. Thereafter, each of themasses of enhanced viscosity slowly eroded over various extended timeperiods.

Applicants specifically incorporate the entire contents of all citedreferences in this disclosure. Further, when an amount, concentration,or other value or parameter is given as either a range, preferred range,or a list of upper preferable values and lower preferable values, thisis to be understood as specifically disclosing all ranges formed fromany pair of any upper range limit or preferred to value and any lowerrange limit or preferred value, regardless of whether ranges areseparately disclosed. Where a range of numerical values is recitedherein, unless otherwise stated, the range is intended to include theendpoints thereof, and all integers and fractions within the range. Itis not intended that the scope of the invention be limited to thespecific values recited when defining a range.

Other embodiments of the present invention will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present invention disclosed herein. It is intended thatthe present specification and examples be considered as exemplary onlywith a true scope and spirit of the invention being indicated by thefollowing claims and equivalents thereof.

What is claimed is: 1: An injectable ophthalmic composition, comprising:a therapeutic agent; complexing agent in the composition at aconcentration that is at least 0.01 w/v % but no greater than 10 w/v %of the composition wherein, upon injection into a vitreous humor of aneye of a human, the complexing agent forms a complex with endogenoushyaluronic acid, collagen or both to form a mass of enhanced viscositywithin the vitreous humor and wherein the complexing agent is positivelycharged and the complexing agent is selected from the group consistingof a polyamino acid, a cationic derivatized galactomannan polymer and aquaternary copolymer; and water; wherein the mass of enhanced viscositybreaks down in the vitreous humor to release the therapeutic agentand/or the therapeutic agent diffuses out of the mass of is enhancedviscosity over an extended period of time of at least 8 hours andwherein, upon formation, the mass of enhanced viscosity has a viscositygreater than the viscosity of the injectable composition at the time ofinjection and wherein the composition is contained within a syringe, thesyringe having a needle suitable for intravitreal injection. 2: Thecomposition as in claim 1 wherein the therapeutic agent is a protein orpeptide. 3: The composition as in claim 1 wherein the therapeutic agentis hydrophilic. 4: The composition as in claim 1 wherein the therapeuticagent is hydrophobic and entrapped as nanoparticles, submicronparticles, microparticles or a combination thereof 5: The composition asin claim 1 wherein the density of the mass, upon formation, is less than5% higher or lower than the density of the vitreous fluid. 6: Thecomposition as in claim 5 wherein the mass moves no more than 5millimeters during at least 50% of the extended period of time. 7: Thecomposition as in claim 1 wherein the extended period of time is atleast 20 days. 8: The composition as in claim 1 wherein the compositionis free of hyaluronic acid. 9: An injectable ophthalmic composition,comprising: a therapeutic agent; complexing agent in the composition ata concentration that is at least 0.01 w/v % but no greater than 10 w/v %of the composition wherein, upon injection into a vitreous humor of aneye of a human, the complexing agent forms a complex with endogenoushyaluronic acid, collagen or both to form a mass of enhanced viscositywithin the vitreous humor and wherein the complexing agent is positivelycharged and the complexing agent is selected from the group consistingof a polyamino acid, a cationic derivatized galactomannan polymer and aquaternary copolymer; and water; wherein the composition is containedwithin a syringe, the syringe having a needle is suitable forintravitreal injection and wherein the mass of enhanced viscosity breaksdown in the vitreous humor to release the therapeutic agent and/or thetherapeutic agent diffuses out of the mass of enhanced viscosity over anextended period of time and wherein the extended time period is at least20 days and wherein, upon formation, the mass of enhanced viscosity hasa viscosity greater than the viscosity of the injectable composition atthe time of injection. 10: The composition as in claim 9 wherein thetherapeutic agent is a protein or peptide. 11: The composition as inclaim 9 wherein the therapeutic agent is hydrophilic. 12: Thecomposition as in claim 9 wherein the therapeutic agent is hydrophobicand entrapped as nanoparticles, submicron particles, microparticles or acombination thereof and wherein the composition is free of hyaluronicacid. 13: The composition as in claim 9 wherein the complexing agent issuch that the mass forms with a density that enables the mass to remainsubstantially stationary relative to the eye for a substantial portionof the extended period of time and wherein the substantial portion is atleast 50% of the extended period of time and wherein substantiallystationary means that a center of the mass moves no more than 5millimeters during the substantial portion of the extended period oftime. 14: A method or forming and/or administering an intravitrealinjection, the method comprising: filling a syringe with a composition,the composition including: i. a therapeutic agent; ii. an amount ofcomplexing agent sufficient to form a mass of enhanced viscosity withina vitreous humor of an eye of a human upon injection of the compositioninto the eye; and iii. water; and injecting the composition into an eyeof a human with the syringe and allowing the io mass of enhancedviscosity to break down in the vitreous humor to release the therapeuticagent and/or allow the therapeutic agent to diffuses out of the mass ofenhanced viscosity over an extended period of time. 15: A method as inclaim 14 wherein: i. the complexing agent is positively charged and isselected from galactomannan polymer, a poly-amino acid, a quaternaryammonium compound, a cellulosic polymer or a combination thereof; ii.the amount of complexing agent is at least 0.01 w/v % but no greaterthan 10 w/v % of the composition; iii. the complexing agent forms acomplex with endogenous hyaluronic acid, collagen or both for formingthe mass; and iv. the extended time period is at least 20 days.